CN111253558B - Hybrid polymerization amphiphilic block copolymer and synthesis method and application thereof - Google Patents

Hybrid polymerization amphiphilic block copolymer and synthesis method and application thereof Download PDF

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CN111253558B
CN111253558B CN201911144340.0A CN201911144340A CN111253558B CN 111253558 B CN111253558 B CN 111253558B CN 201911144340 A CN201911144340 A CN 201911144340A CN 111253558 B CN111253558 B CN 111253558B
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lactide
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俞麟
吴凯婷
丁建东
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Zhuhai Fudan Innovation Research Institute
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Abstract

The invention belongs to the field of biomedical high polymer materials, discloses a hybrid polymerization amphiphilic block copolymer and a synthesis method and application thereof, and particularly relates to a method for obtaining an amphiphilic block copolymer by initiating macromolecular polyethylene glycol and carrying out hybrid polymerization on methyl methacrylate, lactone and a lactide monomer. The hybrid polymerization amphiphilic block copolymer disclosed by the invention has controllable molecular weight and molecular weight distribution and a special molecular structure, and side chain functional groups such as ester groups and the like can be introduced into a polyester chain segment. The polymer is obtained by a one-step hybridization copolymerization method of lactone and copulate monomers such as methyl methacrylate, caprolactone and the like by using macromolecules such as polyethylene glycol, polyethylene glycol monomethyl ether and the like as an initiator in the presence of a catalyst phosphazene base (t-BuP 4). The hybrid polymerization amphiphilic block copolymer can form micelles in aqueous solution, can be used as a novel polyester biomedical material, and is potentially applied to drug loading and delivery.

Description

Hybrid polymerization amphiphilic block copolymer and synthesis method and application thereof
Technical Field
The invention relates to a synthesis method of a hybrid polymerization block copolymer, in particular to a hybrid polymerization amphiphilic block copolymer and a synthesis method and application thereof, and particularly relates to a method for obtaining the amphiphilic block copolymer by initiating by macromolecular polyethylene glycol and carrying out hybrid polymerization on methyl methacrylate and lactone or a lactide monomer.
Background
The biomedical polymer material has the advantages of good biocompatibility, easy-to-adjust degradability and the like, is an important content of biomedical material research, and has wide application prospects in the fields of drug delivery systems, tissue engineering and the like. Among them, the amphiphilic block copolymer is one of the most widely used biomedical polymer materials. However, most of them are polyester materials, and their structures are relatively simple and not enough to load various drugs with different structural functions. Therefore, the introduction of certain functional groups on the side chain of the block copolymer is of great significance in clinical practice and scientific research.
Copolymerization of various cyclic esters with functional side groups is certainly a good way to obtain such materials, but since there are fewer cyclic esters and the types of side groups thereon are more limited, another more challenging and potential strategy is to copolymerize vinyl monomers and cyclic ester monomers in a hybrid manner.
The polymerization reaction is the core of polymer synthesis and mainly comprises two main types, namely step-by-step polymerization and chain polymerization, wherein the former is generally the polymerization reaction of a bifunctional terminal group monomer, and the latter comprises polymerization reaction types such as anion polymerization, cation polymerization, coordination polymerization, free radical polymerization and the like, and the common polymerization types comprise double bond addition polymerization of a vinyl monomer, ring-opening polymerization of a cyclic ester monomer and the like. The polymerization reaction includes homopolymerization and copolymerization, and the polymerization of the same monomer is homopolymerization while the copolymerization of two or more monomers is copolymerization. Generally, monomers for polymerization reaction are generally of the same type and are polymerized according to the same polymerization mechanism, while different types of monomers have greatly different activities and different polymerization mechanisms, so that hybrid polymerization is difficult and very challenging.
Hybrid polymerization is a polymerization reaction which is newly developed in recent years, and international names of the polymerization reaction are not fixed, and hybrid copolymerization or hybrid copolymerization are also known, but the reactions referred to by the concepts are different. Professor tsunami of Qinghua university in 2000 researches on free radical polymerization and cationic hybrid copolymerization (acrylate and epoxy compound photocuring system) and free radical polymerization and polycondensation hybrid copolymerization (acrylate and isocyanate photocuring system), and finds that hybrid copolymerization can form a high-molecular alloy (rather than a polymer) in situ and possibly obtain an interpenetrating network structure, so that a polymerization product has better comprehensive performance.
In 1982, baily et al successfully synthesized a high molecular weight polymer with ten thousand molecular weights by free radical hybrid polymerization of three monomers, 2-methylene-1, 3-dioxepane (MDO), methyl Methacrylate (MMA) and N, N-dimethylaminoethyl methacrylate (DMAEMA), using AIBN, BPO as initiators and under photo-initiation conditions.
In 2012, zhang Guangdong professor of university of southern China's science found that Caprolactone (CL) and Methyl Methacrylate (MMA) in phosphazene base (t-BuP) 4 ) Under catalysis, anionic hybrid copolymerization occurs at room temperature to form a random copolymer. They have only attempted to use the more reactive small molecule alcohols as initiators and have found that polymers initiated with dihydric alcohols have a significantly broader molecular weight distribution than monohydric alcohols.
2013, aoshima et al reported on small organic molecules B (C) 6 F 5 ) 3 (Lewis acid) catalyzed copolymerization of Vinyl Ether (VE) with isobutylene oxide (IBO), a cationic hybrid copolymerization of vinyl addition and ring opening polymerization. However, the molecular weight of the polymer is low and the distribution is wide.
At present, the methods of anion and cation hybrid polymerization are applied more, but the types of monomers suitable for free radical hybrid polymerization are few. In addition, such polymerization reactions are less studied and the reaction conditions are still unknown and need to be explored. The method applies anion hybrid polymerization for the first time, takes macromolecular polyethylene glycol as an initiator, and synthesizes amphiphilic block copolymer by using lactone or copperas monomers such as methyl methacrylate, caprolactone and the like under the catalysis of phosphazene base, and is suitable for the field of biomedical materials. Unlike conventional polyester materials, the polymer obtained by the method can introduce functional side groups into a polyester block, and is a novel polyester material.
Disclosure of Invention
In view of the above, the present invention provides a hybrid polymeric amphiphilic block copolymer and a synthetic method thereof, which is a new synthetic route for amphiphilic hybrid polymeric block copolymers.
In order to achieve the purpose, the invention adopts the following technical scheme:
a hybrid polymeric amphiphilic block copolymer having the structural formula:
Figure BDA0002281763890000021
wherein, the block A is a methyl methacrylate unit, and the block B is a lactone or lactide unit; co-denotes random copolymerization, the random copolymer of the AB diblock is called hybrid polyester block; the block R is a polyethylene glycol or polyethylene glycol monomethyl ether macroinitiator block.
Illustratively, the amphiphilic block copolymer has a molecular weight of 2000 to 10000.
Preferably, the molecular weight of the amphiphilic block copolymer is 2000-10000; the content of the block R is 10-90mol%, and the content of the hybrid polyester block is 90-10mol%; wherein the content of the block A in the hybrid polyester block is 10 to 90mol%, and the content of the block B in the hybrid polyester block is 90 to 10mol%; the block R is macromolecular linear polyethylene glycol or linear polyethylene glycol monomethyl ether with the molecular weight of 500-8000, and the block B is at least one of poly DL-lactide, poly D-lactide, poly L-lactide, polyglycolide, poly epsilon-caprolactone, poly delta-caprolactone and poly delta-valerolactone.
The invention discloses a synthesis method of a hybrid polymerization amphiphilic block copolymer, wherein the amphiphilic block copolymer is obtained by taking linear macromolecular polyethylene glycol or polyethylene glycol monomethyl ether as an initiator and performing one-step hybrid copolymerization on vinyl monomers, namely methyl methacrylate and lactone or a copter monomer at room temperature under the action of a phosphazene base catalyst.
It is worth to say that the amphiphilic block copolymer is obtained by a one-step hybridization copolymerization method, the molecular weight and the molecular weight distribution of the synthesized polymer are controllable, and the problem of copolymerization among monomers with different polymerizable functional groups is solved. Meanwhile, functional side groups (ester functional groups) are introduced into the polyester block of the amphiphilic block copolymer by a hybrid polymerization method to serve as a novel polyester material for drug loading and delivery.
Preferably, the hybrid copolymerization reaction step is as follows:
(1) Dissolving macromolecular polyethylene glycol in an organic solvent, and removing water by azeotropy to obtain an anhydrous organic solvent solution;
(2) Cooling the organic solvent solution to room temperature, adding anhydrous methyl methacrylate and lactone or a lactide monomer in the inert gas atmosphere, and then adding a phosphazene base catalyst to obtain a mixed reaction solution;
(3) Sealing the mixed reaction solution in an oil bath at a preset temperature for reaction for preset time, and terminating polymerization by using a terminator to obtain a product solution;
(4) And settling the product solution, pouring supernatant liquid, and drying in vacuum to remove the solvent to obtain the amphiphilic block copolymer.
It is worth to be noted that, in the synthesis method of the hybrid polymerization amphiphilic block copolymer provided by the invention, the solution of the macromolecular polyethylene glycol compound is usually a toluene solution of the polyethylene glycol compound, and the catalyst is the phosphazene base (t-BuP) purchased from sigma 4 ) Catalyst, and dissolving the phosphazene base (t-BuP) 4 ) The solvent of the catalyst is n-hexane solvent, the methyl methacrylate is obtained by calcium hydride reflux dehydration treatment and reduced pressure distillation, and the lactone or diester monomer is obtained by calcium hydride reflux dehydration treatment and reduced pressure distillation.
Wherein the phosphazene base (t-BuP) 4 ) The structural formula of the catalyst is as follows:
Figure BDA0002281763890000041
in addition, the post-treatment operation steps of the reaction system in the synthesis method of the hybrid polymerization amphiphilic block copolymer mainly comprise: the method comprises a reaction termination step, a sedimentation step, a filtration step and a drying step, wherein a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1.
Preferably, the predetermined temperature in the step (3) is 25-50 ℃, the predetermined time is 1-12h, the concentration of the mixed reaction solution is 4.0-8.0mol/L, and the concentration of the phosphazene base catalyst is 0.0016-0.016mol/L.
Further preferably, the predetermined temperature in the step (3) is 25 ℃, the predetermined time is 6h, and the concentration of the mixed reaction solution is 8.0mol/L, wherein the concentration of the phosphazene base catalyst is 0.016mol/L.
Preferably, the organic solvent is toluene, the phosphazene base catalyst is a commercially available catalyst, and the concentration of the catalyst is 0.8mol/L.
Preferably, the macromolecular polyethylene glycol is hydroxyl-terminated polyethylene glycol or polyethylene glycol monomethyl ether, and the lactone or lactide monomer is at least one of DL-lactide, D-lactide, L-lactide, glycolide, epsilon-caprolactone, delta-caprolactone and delta-valerolactone;
further preferably, the amphiphilic block copolymer includes a poly (e-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, a poly (delta-valerolactone/methyl methacrylate) -polyethylene glycol copolymer, a poly (delta-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, a poly (DL-lactide/methyl methacrylate) -polyethylene glycol copolymer, a poly (L-lactide/methyl methacrylate) -polyethylene glycol copolymer, a poly (D-lactide/methyl methacrylate) -polyethylene glycol copolymer or a poly (glycolide/methyl methacrylate) -polyethylene glycol copolymer.
Preferably, the amphiphilic block copolymer has a molar ratio of methyl methacrylate to lactone or lactide monomer of 1.
According to the synthesis method of the hybrid polymerization amphiphilic block copolymer, because the methyl methacrylate monomer and the lactone or the lactide monomer are added for copolymerization, the amphiphilic block copolymer prepared by the method is not in a powder shape similar to PCL (polycaprolactone) or a hard glass shape similar to PMMA (polymethyl methacrylate), and is a white viscous polymer.
Further, since two or more segments having different structures are present in the amphiphilic block polymer, a copolymer having a specific chemical structure and a molecular weight can be synthesized as needed. In addition, after the amphiphilic block copolymer is dissolved in water, a high-molecular micelle consisting of a hydrophilic shell and a lipophilic core can be spontaneously formed, so that the amphiphilic block copolymer can entrap a drug for drug delivery. The hybrid polymerization amphiphilic block copolymer disclosed by the invention can form micelles with the size of about 40nm by dissolving in water.
Furthermore, the phosphazene base catalyst is also a special catalyst in the method, and most other catalysts do not have the capability of catalyzing the hybrid polymerization of methyl methacrylate and lactone or lactide monomers to form a copolymer. The hybrid polymeric amphipathic segmented copolymer synthesized by the method can be quickly dissolved in water to form colorless transparent solution. It is to be noted that when the ratio of methyl methacrylate to caprolactone monomers is less than 1: when 8, quenching is required for dissolution.
It is also an object of the present invention to provide the use of said amphiphilic block copolymers in the field of drug loading and delivery.
Further preferably, ester group functional groups are introduced into the side chains of the polyester block of the amphiphilic block copolymer to form micelles or gels for drug loading and delivery.
Compared with the prior art, the hybrid polymerization amphiphilic block copolymer and the synthesis method and the application thereof disclosed by the invention have the following excellent effects:
the molecular weight and molecular weight distribution of the hybrid polymerization amphiphilic block copolymer provided by the invention are controllable, the repeating units on the chain segments have the characteristic of hybrid copolymerization, and the polyester blocks contain functional side groups such as ester groups and the like to form a novel polyester material, so that the hybrid polymerization amphiphilic block copolymer is suitable for the field of biomedical materials and can be potentially applied to drug loading and delivery.
In addition, the invention takes macromolecular polyethylene glycol as an initiator, and obtains the amphiphilic block copolymer by one-step hybridization copolymerization of vinyl monomer methyl methacrylate and lactone or a copoite monomer at room temperature under the catalysis of a phosphazene base catalyst, and the method has the advantages of simplicity, mildness, safety, environmental protection, simple separation and purification and the like, and is suitable for large-scale production; functional side groups can be introduced into the polyester block of the synthesized amphiphilic block copolymer to form a novel polyester material, the novel polyester material is suitable for the field of biomedical materials, the controllability of polymerization reaction is strong, and the molecular weight distribution of the synthesized polymer are controllable, so that a convenient and feasible preparation means is provided for developing the amphiphilic block copolymer for drug loading and delivery through hybrid copolymerization synthesis.
Meanwhile, the repeating units on the chain segments of the hybrid polymerization block copolymer synthesized by the method disclosed by the invention have the characteristic of hybrid copolymerization, and the synthesis method is a novel polymerization method for copolymerizing two different types of monomers, and functional groups such as ester groups and the like can be introduced into the side chains of the polymer, so that the material can be conveniently applied to the field of biomedicine.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 shows P3 co synthesized in example 3 of the present inventionOf polymers 1 H NMR spectrum.
FIG. 2 is a GPC chart of a P6 copolymer synthesized in example 6 of the present invention.
FIG. 3 is a DSC of the P6 copolymer synthesized in example 6 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention should not be construed as being limited thereto, and the insubstantial modifications and variations of the present invention as shown in the above-described summary of the invention are considered to fall within the scope of the invention by those skilled in the art.
The invention discloses a hybrid polymerization amphiphilic block copolymer, which has the structural formula as follows:
Figure BDA0002281763890000071
wherein, the block A is a methyl methacrylate unit, and the block B is a lactone or lactide unit; co-denotes random copolymerization, the random copolymer of the AB diblock is called hybrid polyester block; the block R is a polyethylene glycol or polyethylene glycol monomethyl ether macromolecular initiator block.
In order to further optimize the technical scheme, the molecular weight of the amphiphilic block copolymer is 2000-10000; the content of the block R is 10-90mol%, and the content of the hybrid polyester block is 90-10mol%; wherein the content of the block A in the hybrid polyester block is 10-90mol%, and the content of the block B in the hybrid polyester block is 90-10mol%; and the block R is macromolecular linear polyethylene glycol or linear polyethylene glycol monomethyl ether with the molecular weight of 500-8000, and the block B is at least one of poly DL-lactide, poly D-lactide, poly L-lactide, polyglycolide, poly epsilon-caprolactone, poly delta-caprolactone and poly delta-valerolactone.
In addition, the embodiment of the invention discloses a synthesis method of amphiphilic block copolymer with controllable molecular weight and molecular weight distribution and application of anion hybrid polymerization, which specifically comprises the following steps:
(1) Dissolving macromolecular polyethylene glycol in toluene, and removing water by azeotropy to obtain an anhydrous PEG toluene solution;
(2) Cooling the toluene solution to room temperature, adding anhydrous methyl methacrylate and lactone or a diester monomer in the inert gas atmosphere, and then adding a phosphazene base catalyst to obtain a mixed reaction solution;
(3) Sealing the mixed reaction solution in an oil bath at a preset temperature for reaction for preset time, and terminating polymerization by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1;
(4) And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring supernatant liquid, and performing vacuum drying to remove the solvent to obtain the amphiphilic block copolymer.
In order to further optimize the technical scheme, the preset temperature in the step (3) is 25-50 ℃, the preset time is 1-12h, and the concentration of the mixed reaction solution is 4.0-8.0mol/L, wherein the concentration of the phosphazene base catalyst is 0.0016-0.016mol/L.
In order to further optimize the technical scheme, the macromolecular polyethylene glycol is double-end hydroxyl polyethylene glycol or polyethylene glycol monomethyl ether, and the lactone or lactide monomer is at least one of DL-lactide, D-lactide, L-lactide, glycolide, epsilon-caprolactone, delta-caprolactone and delta-valerolactone.
In order to further optimize the above technical solution, the amphiphilic block copolymer comprises poly (epsilon-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (delta-valerolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (delta-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (DL-lactide/methyl methacrylate) -polyethylene glycol copolymer, poly (L-lactide/methyl methacrylate) -polyethylene glycol copolymer, poly (D-lactide/methyl methacrylate) -polyethylene glycol copolymer or poly (glycolide/methyl methacrylate) -polyethylene glycol copolymer.
In order to further optimize the technical scheme, the mole ratio of methyl methacrylate to lactone or lactide monomer in the amphiphilic block copolymer is 1-9.
In order to make the technical means, creation characteristics, and the achieved objects and effects of the present invention easy to understand, the following embodiments and drawings are used to specifically describe the synthesis method and the application of the hybrid polymeric amphiphilic block copolymer of the present invention.
All reactions in the following examples were carried out under an argon atmosphere, unless otherwise specified. All starting materials and solvents are commercial reagents, except where noted. Calcium hydride (CaH) for Methyl Methacrylate (MMA) 2 ) Stirring overnight at normal temperature under high-purity argon atmosphere, distilling under reduced pressure, collecting in an eggplant-shaped bottle, sealing, placing in a refrigerator at-20 deg.C, and taking for subsequent test. Calcium hydride (CaH) for epsilon-caprolactone (epsilon-CL), delta-caprolactone (delta-CL) and delta-valerolactone (delta-VL) 2 ) Stirring overnight at normal temperature under high-purity argon atmosphere, distilling under reduced pressure, collecting in a eggplant-shaped bottle, sealing, placing in a cool and dry place, and taking for subsequent experiments. Recrystallizing DL-lactide (DL-LA), D-lactide (D-LA), L-lactide (L-LA) and Glycolide (GA), and storing in refrigerator at-20 deg.C.
In the following examples, the amount of the raw materials such as polyethylene glycol, methyl methacrylate and caprolactone is in mmol; the unit of the solvent dosage is mL; the reaction temperature is given in units of ℃. Characterized by NMR and GPC, the former being as 1 H NMR standard file is used as reference, the number of scanning times is set to be 16, nuclear magnetic hydrogen spectrum is obtained, and the nuclear magnetic hydrogen spectrum is obtained by using PS as stationary phase and THF as mobile phase, the outflow time is 36 minutes, and the temperature is 40 ℃, so that gel permeation chromatography is obtained.
Example 1
0.5mmol of polyethylene glycol (molecular weight is 1000,0.500g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. Bottle for reactionThe heating was stopped when about 5mL of toluene remained. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 2mmol (0.2 g) of anhydrous methyl methacrylate and 8mmol (0.912 g) of anhydrous epsilon-caprolactone monomer into the system by using an injector under the protection of argon, and finally adding 0.1mL of t-BuP through the injector 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction in an oil bath at 25 ℃ for 12 hours, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P1). The solid is a hybrid polymerization block copolymer, and is sealed and stored in a refrigerator at the temperature of-20 ℃.
The mass of the hybrid polymeric block copolymer P1 obtained in this example was 1.22g, and the yield was 75%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 3000 and 5460, respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.82.
Example 2
0.5mmol of polyethylene glycol monomethyl ether (the molecular weight is 550,0.275g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping argon for 3 times, adding 2mmol (0.2 g) of anhydrous methyl methacrylate and 16mmol (1.824 g) of anhydrous epsilon-caprolactone monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 Catalyst n-hexane solution to obtain mixed solution. The mixed solution is subjected to tube sealing reaction in an oil bath at 25 ℃ for 12 hours, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P2). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
Obtained in this exampleThe mass of the hybrid polymeric block copolymer P2 was 2.21g, and the yield was 80%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 4510 and 7800, respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.73. By passing 1 The molecular weight of the polymer was 550-3910 by H NMR.
Example 3
0.5mmol of polyethylene glycol monomethyl ether (with the molecular weight of 750,0.375g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping argon for 3 times, adding 9mmol (0.9 g) of anhydrous methyl methacrylate and 1mmol (0.114 g) of anhydrous epsilon-caprolactone monomer into the system by using an injector under the protection of argon, and finally adding 0.5mL of t-BuP through the injector 4 Catalyst n-hexane solution to obtain mixed solution. The mixed solution is subjected to tube sealing reaction in an oil bath at 25 ℃ for 12 hours, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. The product solution was added dropwise to glacial ethyl ether for settling treatment, and after pouring out the supernatant, the solvent was removed by vacuum drying to give a pale yellow solid product (P3). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
The mass of the hybrid polymeric block copolymer P3 obtained in this example was 1.18g, and the yield was 85%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 2930 and 5010, respectively, molecular weight distribution coefficient (M) w /M n ) Was 1.71. By passing 1 H NMR analysis showed that the molecular weight of the polymer was 750-2180.
Example 4
0.5mmol of polyethylene glycol monomethyl ether (with the molecular weight of 750,0.375g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, and performing argon protection18mmol (1.8 g) of anhydrous methyl methacrylate and 18mmol (2.052 g) of anhydrous delta-caprolactone monomer are added into the system by a syringe, and finally 0.1mL of t-BuP is added through the syringe 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P4). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
The mass of the hybrid polymeric block copolymer P4 obtained in this example was 3.59g, and the yield was 85%. As shown in FIG. 1, the amphiphilic block copolymer is structurally characterized by nuclear magnetic resonance hydrogen spectroscopy, and the number average molecular weight (M) and the weight average molecular weight (M) of the polymer are measured by GPC (THF is used as a mobile phase and PS is used as a standard sample) n ，M w ) 8020 and 11790, respectively, molecular weight distribution coefficient (M) w /M n ) Was 1.47. By passing 1 The molecular weight of the polymer is 750-7210 by HNMR determination.
Example 5
0.5mmol of polyethylene glycol monomethyl ether (the molecular weight is 750,0.375 g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 2mmol (0.2 g) of anhydrous methyl methacrylate and 8mmol (0.912 g) of anhydrous epsilon-caprolactone monomer into the system by using an injector under the protection of argon, and finally adding 0.1mL of t-BuP through the injector 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 1h in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a colorless transparent liquid product (P5). The liquid is hybrid polymer block copolymer, and can be stored at-20 deg.C under sealed conditionA refrigerator.
The mass of the hybrid polymeric block copolymer P5 obtained in this example was 0.42g, and the yield was 28%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 1910 and 3210, respectively, molecular weight distribution coefficient (M) w /M n ) Was 1.68. By passing 1 The molecular weight of the polymer is 750-1210 by HNMR determination.
Example 6
0.5mmol of polyethylene glycol (molecular weight is 1000,0.500g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping argon for 3 times, adding 5mmol (0.500 g) of anhydrous methyl methacrylate and 10mmol (1.140 g) of anhydrous epsilon-caprolactone monomer into the system by using an injector under the protection of argon, and finally adding 0.1mL of t-BuP through the injector 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P6). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
The mass of the hybrid polymeric block copolymer P6 obtained in this example was 1.82g, and the yield was 85%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as the mobile phase and PS as the standard) as shown in FIG. 2 n ，M w ) 4573 and 6022, respectively, molecular weight distribution coefficient (M) w /M n ) Was 1.32.
Furthermore, as shown in FIG. 3, the DSC curve shows the melting endotherm and crystallization exotherm of the polymer P6, and it can be seen from the temperature rise curve that there is a melting endotherm peak at 20-30 ℃ which is assigned to the melting endotherm of the PEG block, a melting endotherm peak at 30-40 ℃ which represents the melting endotherm of PMMA in the hybrid polyester block, and a sharp peak at 40-50 ℃ which is assigned to the melting endotherm of PCL in the hybrid polyester block; while an exothermic peak at-3-10 ℃ can be observed in the cooling process, which represents the crystallization exothermic of PCL in the hybrid polyester block, the exothermic peak at-20-0 ℃ belongs to PMMA in the polyester block, and the crystallization of the PEG block is not obvious.
Example 7
0.5mmol of polyethylene glycol (molecular weight is 1000,0.500g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. The toluene solution is cooled to room temperature, argon is pumped for 3 times, 18mmol (1.800 g) of anhydrous methyl methacrylate and 27mmol (2.70 g) of anhydrous delta-valerolactone monomer are added into the system by a syringe under the protection of argon, and finally 0.1mL of t-BuP is added into the system by the syringe 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P7). The solid is a hybrid polymerization block copolymer, and is sealed and stored in a refrigerator at the temperature of-20 ℃.
The mass of the hybrid polymeric block copolymer P6 obtained in this example was 4.25g, and the yield was 85%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 9270 and 13070, respectively, molecular weight distribution coefficient (M) w /M n ) Was 1.41.
Example 8
0.5mmol of polyethylene glycol (molecular weight 2000, 1.000g) is weighed into a reaction flask, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping out argon for 3 times, adding 0.5mmol (0.05 g) of anhydrous methyl methacrylate and 0.5mmol (0.072 g) of anhydrous DL-lactide monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 CatalysisAdding n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. The product solution was added dropwise to glacial ethyl ether for sedimentation treatment, and the supernatant was poured and vacuum-dried to remove the solvent, yielding a colorless transparent liquid (P8). The product is a hybrid polymerization block copolymer, and is sealed and stored in a refrigerator at the temperature of-20 ℃.
The mass of the hybrid polymeric block copolymer P8 obtained in this example was 0.84g, and the yield was 75%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 1810 and 2590 respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.43.
Example 9
0.5mmol of polyethylene glycol (molecular weight is 4000,2.000g) is weighed into a reaction flask, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 15.0mmol (1.5 g) of anhydrous methyl methacrylate and 15.0mmol (1.71 g) of anhydrous D-lactide monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 Catalyst n-hexane solution to obtain mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P9). The solid is a hybrid polymerization block copolymer, and is sealed and stored in a refrigerator at the temperature of-20 ℃.
The mass of the hybrid polymeric block copolymer P9 obtained in this example was 3.6g, and the yield was 70%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 9340 and 13820, respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.48.
Example 10
0.5mmol of polyethylene glycol (with the molecular weight of 5000, 2.500g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 2.5mmol (0.25 g) of anhydrous methyl methacrylate and 5.0mmol (0.72 g) of anhydrous L-lactide monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. And dropwise adding the product solution into glacial ethyl ether for settling treatment, pouring a supernatant, and performing vacuum drying to remove the solvent to obtain a white solid product (P10). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
The mass of the hybrid polymeric block copolymer P10 obtained in this example was 2.95g, and the yield was 85%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 6840 and 9090, respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.33.
Example 11
0.5mmol of polyethylene glycol (molecular weight is 8000,4.000g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 1.00mmol (0.100 g) of anhydrous methyl methacrylate and 4.00mmol (0.464 g) of anhydrous glycolide monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 Catalyst n-hexane solution to obtain mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. Dropping the product solution into the glacial ethyl ether for sedimentationAfter treatment, the supernatant was poured off and the solvent was removed by vacuum drying, the product was obtained as a white solid (P11). The solid is a hybrid polymerization block copolymer and is stored in a refrigerator at the temperature of minus 20 ℃ in a sealing way.
The mass of the hybrid polymeric block copolymer P11 obtained in this example was 3.6g, and the yield was 80%. The number average and weight average molecular weights (M) of the polymers were determined by GPC (using THF as mobile phase and PS as standard) n ，M w ) 9360 and 12820, respectively, molecular weight distribution coefficient (M) w /M n ) Is 1.37.
Example 12
0.5mmol of polyethylene glycol (molecular weight is 1000,0.500g) is weighed into a reaction bottle, 20mL of toluene is added, and azeotropic dehydration is carried out under the condition of argon protection. And stopping heating when about 5mL of toluene remains in the reaction bottle. Cooling the toluene solution to room temperature, pumping and replacing argon for 3 times, adding 11.68mmol (1.004 g) of anhydrous methacrylic acid and 11.68mmol (1.332 g) of anhydrous epsilon-caprolactone monomer into the system by using a syringe under the protection of argon, and finally adding 0.1mL of t-BuP through the syringe 4 And (4) catalyst n-hexane solution to obtain a mixed solution. The mixed solution is subjected to tube sealing reaction for 6 hours in an oil bath at 25 ℃, and after the polymerization is terminated by using a mixed solution of hydrochloric acid and methanol (the volume ratio of the hydrochloric acid to the methanol is 1. The product solution was added dropwise to glacial ethyl ether for settling treatment, and no product was obtained. Indicating that methacrylic acid and epsilon-caprolactone could not be polymerized.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (9)

1. A hybrid polymeric amphiphilic block copolymer having the structural formula:
Figure 689412DEST_PATH_IMAGE001
；
wherein, the block A is a methyl methacrylate unit, and the block B is a lactone or lactide unit; co-denotes random copolymerization, the random copolymer of the AB diblock is called hybrid polyester block; the block R is a polyethylene glycol or polyethylene glycol monomethyl ether macroinitiator block; m and n represent the number of repeating units;
the molecular weight of the amphiphilic block copolymer is 2000-10000; the content of the block R is 10-90mol%, and the content of the hybrid polyester block is 90-10mol%; wherein the content of the block A in the hybrid polyester block is 10-90mol%, and the content of the block B in the hybrid polyester block is 90-10 mol%.
2. The hybrid polymeric amphiphilic block copolymer according to claim 1, wherein the block R is macromolecular linear polyethylene glycol or linear polyethylene glycol monomethyl ether with molecular weight of 500-8000.
3. The hybrid polymeric amphiphilic block copolymer according to claim 1, wherein the block B is at least one of poly DL-lactide, poly D-lactide, poly L-lactide, polyglycolide, poly epsilon-caprolactone, poly delta-caprolactone and poly delta-valerolactone.
4. The method for synthesizing hybrid polymeric amphiphilic block copolymer according to any one of claims 1 to 3, wherein the hybrid copolymerization reaction steps are as follows:
(1) Dissolving macromolecular polyethylene glycol in an organic solvent, and removing water by azeotropy to obtain an anhydrous organic solvent solution;
(2) Cooling the organic solvent solution to room temperature, adding anhydrous methyl methacrylate and lactone or a lactide monomer in the inert gas atmosphere, and then adding a phosphazene base catalyst to obtain a mixed reaction solution;
(3) Sealing the mixed reaction solution in an oil bath at a preset temperature for reaction for preset time, and terminating polymerization by using a terminator to obtain a product solution;
(4) Settling the product solution, pouring supernatant, and drying in vacuum to remove the solvent to obtain the amphiphilic block copolymer;
the macromolecular polyethylene glycol is double-end hydroxyl polyethylene glycol or polyethylene glycol monomethyl ether.
5. The method as claimed in claim 4, wherein the predetermined temperature in step (3) is 25-50 ℃, the predetermined time is 1-12h, the concentration of the mixed reaction solution is 4.0-8.0mol/L, and the concentration of the phosphazene base catalyst is 0.0016-0.016mol/L.
6. The method for synthesizing the hybrid polymeric amphiphilic block copolymer as claimed in claim 4, wherein the lactone or lactide monomer is at least one of DL-lactide, D-lactide, L-lactide, glycolide, epsilon-caprolactone, delta-caprolactone and delta-valerolactone; and the amphiphilic block copolymer comprises poly (epsilon-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (delta-valerolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (delta-caprolactone/methyl methacrylate) -polyethylene glycol copolymer, poly (DL-lactide/methyl methacrylate) -polyethylene glycol copolymer, poly (L-lactide/methyl methacrylate) -polyethylene glycol copolymer, poly (D-lactide/methyl methacrylate) -polyethylene glycol copolymer or poly (glycolide/methyl methacrylate) -polyethylene glycol copolymer.
7. The method for synthesizing the hybrid polymeric amphiphilic block copolymer as claimed in claim 6, wherein the molar ratio of methyl methacrylate to lactone or lactide monomer in the amphiphilic block copolymer is 1.
8. Use of a hybrid polymeric amphiphilic block copolymer as disclosed in claim 1 or an amphiphilic block copolymer prepared by the synthesis method as described in claim 4 for the preparation of materials in the field of drug loading and delivery.
9. Use of a hybrid polymeric amphiphilic block copolymer according to claim 8, wherein ester group functional groups are introduced in the side chains of the polyester block of the amphiphilic block copolymer for the preparation of drug loading and delivery materials.
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